Throughout this application various publications are referenced. The disclosures of each of these publications in their entireties are hereby incorporated by reference in this application.
Macrophages (MØ) are crucial for human immunodeficiency virus type 1 (HIV) pathogenesis. In addition to their antigen presenting function, these cells appear to be important targets for HIV infection in extravascular tissues. Nearly all primary HIV strains are capable of replication in MØ, and the overwhelming predominance of macrophage (M)-tropic virus strains early in disease suggest that these cells may be involved in virus transmission, particularly for sexually acquired infection.
Substantial work has been accomplished over the last decade to define molecular determinants of M-tropism; identification of particularly the β chemokine receptor CCR5 as an HIV co-receptor required for efficient entry of M-tropic HIV strains into MØ, as well as CD4+ T cells. Specific mechanisms of entry into primary MØ remain poorly defined, however. Although CD4 and CXCR4 are expressed on MØ and can be utilized for entry, viruses that use CD4 and CCR5 (R5 strains) infect MØ more efficiently than those using CD4 and CXCR4 (X4 strains). T-tropic HIV strains that use CD4 and CCR5 that do enter MØ, however, may fail to replicate in an Env-dependent manner. Efficiency of HIV infection may therefore involve cellular factors in addition to CD4 and chemokine receptors.
Treatment of HIV infection dramatically improved in 1996 with the approval of protease inhibitors, and the routine use of combinations of three or four antiretroviral drugs simultaneously. Despite initial success resulting in suppression of virus replication below limits of quantification in the majority of patients (Gulick 1998; Staszewski 1999), limitations of this approach are becoming increasingly apparent. Only about half of patients initiating combination antiretroviral therapy will have a durable virologic response. Response to subsequent regimens is complicated by cross resistance within the available classes of drugs, limited exclusively to protease inhibitors and reverse transcriptase inhibitors. Prototype small molecule inhibitors of chemokine receptor interactions, and of gp41-mediated fusion are directed to envelope-specific events in the HIV life cycle, opening the era of development of a new class of antiretroviral drugs, inhibitors of HIV entry.
Identification of novel cellular factors involved in HIV entry could provide important new therapeutic targets, and expand the arsenal of drugs that can be used in combination to block HIV entry. This class of antiretroviral drugs would still be active in patients who have developed resistance to protease inhibitors and reverse transcriptase inhibitors.